Ether-2-r-substituted benzimidazoles and derivatives and acid addition salts thereof



United States Patent "ice 3,300 505 ETHER-Z-R-SUBSTITUTEDBENZIMIDAZOLES AND DERIVATIVES AND ACID ADDITIQN SALTS THEREOF George de Stevens, Summit, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 1, 1965, Ser. No. 484,433 15 Claims. (Cl. 260-294.8)

This application is a continuation-in-part of application Serial No. 416,647, filed December 7, 1964, now abandoned.

The present invention concerns and has for its object the provision of N-oxygenated benzimidazoles and meth- Ods for their preparation.

More particularly the present invention relates to benzimidazoles of the Formula I:

(L-alkyl-amino (I) in which Ph stands for a 1,2-phenylene radical and R for an aliphatic, araliphatic or aromatic radical, their N-oxides and quaternaries and the salts of these compounds.

The l,2-phenylene radical Ph may be unsubstituted or substituted by one or more than one of the same or of 'diflerent substituents attached to any of the four positions available for substitution. Such substituents are primarily the following: lower alkyl, e.g. methyl, ethyl, n-or iso-propyl or-butyl, etherified hydroxyl, especially lower alkoxy, e.g. methoxy, ethoxy, n-or iso-propyloxy, n-or tert.-butyloxy, lower alkenyloxy, e.g. allyloxy, lower 'alkylenedioxy, e.g. methylenedioxy, esterified hydroxyl,

particularly halogeno, e.g. fluoro, ehloro or bromo, trifiuoromethyl, nitro, unsubstituted or substituted amino, such as di-lower alkylamino, e.g. dimethylamino or diethylamino, acyl, such as lower alkanoyl, e.g. acetyl, propionyl or pivalyl, benzoyl or pyridoyl, e.g. p-toluoyl or nicotinoyl, or sulfamyl.

Above all the 1,2-phenylene radical Ph stands for 1,2- phenylene, (lower a1ky1)-1,2-phenylene, (lower alkoxy)- 1,2-phenylene, (halogeno)-1,2-phenylene, (trifluoromethyl)-1,2-phenylene, (nitro)-l,2 phenylene, (amino) 1,2- phenylene, (di-lower alkylamino)-1,2-phenylene, (lower alkanoyl)-l,2-phenylene or (sulfamyl)-1,2-phenylene.

An aliphatic or araliphatic radical representing R is, for example, lower alkyl, e.g. methyl, ethyl, n-or i-propyl, straight or branched chain butyl, pentyl, hexyl or heptyl bound in any position, lower alkenyl, e.g. allyl or methallyl, cycloalkyl or cycloalkyl-lower alkyl having from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl; cyclopropyl-methyl, cyclopentyl-methyl, 3-cyclopentyl-propyl, cyclohexyl-methyl, 2- cyclohexyl-ethyl or cycloheptylmethyl, cycloalkenyl or cycloalkenyl-lower alkyl having from five to eight, preferably from five to six, ring carbon atoms, e.g. l-cyclopentenyl, l-cyclohexenyl, 3-cyelohexenyl, l-cycloheptenyl, 3-cycloheptenyl or l-cyclooctenyl; l-cyclopentenyl-methyl, 1- cyclohexenylmethyl or 2-(3-cyclohexenyl)-ethyl, or monocyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-or 2-phenylethyl. Said aralkyl radicals may be unsubstituted or substituted in the aromatic moiety by one or more than one of the same or of different substituents attached to any of the positions available for substitution. Such substituents are exemplified by those listed for the 1,2- phenylene radical Ph.

Above all an aliphatic radical R stands for alkyl with 1 to 4 carbon atoms.

Patented Jan. 24, 1967 An aromatic radical R more especially stands for a monocyclic carbocyclic or heterocyclic aryl radical, the latter of which is preferably an azacyclic aryl radical, e.g. a 2-, 3- or 4-pyridyl radical. These aryl radicals may be unsubstituted or substituted by one or more than one of the same or of different substituents attached to any of the positions available for substitution. Such substituents are exemplified by those listed for the 1,2- phenylene radical Ph.

Above all an aromatic radical R stands for phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)- phenyl, (trifluoromethyl)-phenyl, (nitro)-phenyl, (amino)-phenyl, (di-lower alkylamino)-phenyl, (lower alkanoyl)-pheny1 or (sulfamyD-phenyl; pyridyl or (lower alkyl -p yridyl.

The amino-alkyl group in the compounds of the present invention, attached to the oxygen atom, more particularly is a primary, secondary or preferably a tertiary aminolower alkyl group, in which the amino portion is separated from the oxygen atom by at least two carbon atoms. The alkyl chain thereof may be straight or branched and preferably contains 2 to 4 carbon atoms. Examples for the amino-alkyl group are the following: l-amino-ethylp w -p py y y tyl-(4), -pentyl-(5), hexyl-(6), -heptyl-(4) or -2-methyl-propyl-(Z); 2-amin0-propyl-(3), -butyl-(3), -butyl-(4) or -pentyl-(5), 3-amino-butyl-(4) or -pentyl-(5).

The amino-alkyl group preferably contains a secondary or especially a tertiary amino group. It may contain aliphatic, cycloaliphatic, araliphatic or aromatic radicals, such as lower alkyl, alkenyl, alkenylene, aza-, oxa-, or thia-alkylene, monocyclic cyclo-lower alkyl or alkenyl, monocyclic-cyclo-lower alkyl-or alkenyl-lower alkyl, monocyclic carbocyclic aryl-lower alkyl or monocyclic carbocyclic aryl, e.g. those mentioned above. These radicals may be unsubstituted or substituted, the aliphatic radicals especially by free, esterified or etherified hydroxy groups, e.g. those mentioned above and the aryl radicals by those substituents mentioned for Ph.

Examples for such amino groups are the following: monoor d-i-lower alkylamino, e.g. methylamino, dimethylamino, N-methyl-N-ethylamino, ethylamino, diethy-lamino, n-propylamino, di-n-propylaimino, isopropylamino, di-isopropylamino, n-butylamino or di-n-butylamino, hydroxy-lower alkyl-amino, N-(hydroxy-lower alkyl)-N- lower alkyl-amino or di-(hydroxy-lower a1kyl)-amino, in which hydroxyl is separated from the amino nitrogen by at least two carbon atoms, e.g. 2-hydroxyethyl-amino, N- (Z-hydroxyethyl)-N-methylamino or di-(Z-hydroxyethyD- amino, lower alkyleneimino or hydroxy-alkyleneimino, e.g. ethyleneimino, pyrrolidino, Z-methyl-pyrrolidino, piperidino, 2- or 4-met-hyl-piperidino, 3-hydroxyor acetoxy-piperidino, 3-hydroxymethyl-piperidino, 1,6- or 2,5- hexamethyleneimino, 1,7- or 2,6 heptamethyleneim-ino, lower aza-alkyleneirnino, preferably N-lower alkyl-azaalkyleneimino, e.g. piperazino, 4-methyl-, ethyl-, hydroxyethylor acetoxyethyl-piperazino, 3-aza-1,6-hexyleneimino, 3-methyl3-azail,6-hexyleneimino, 4-aza-1,7-'hepty1- eneirnino, 4-methyl-4-aZa-1,7-heptyleneimino, lower oxaor thia-alkyleneimino, e.g. morpholino, 3methyl-morp holino or thiamonpholino, monocyclic cyclo-lower alkylamino or N-cyolo-lower alkyl-N-lower alkyl-amino e.g. cyclopentylamino, cyclohexylamino, N-cyclopentyl-N- methylamino, N-cyclohexyl-N-methylamino or N-cyclohexyl-N-ethylamino, monocyclic cyclo-lower alkyl-lower alkyl-amino, e.g. cyclopentylmethylamino or Z-cyclopentyl-ethylamino, phenyl-lower alkyl-amino or N-lower alkyl- N-phenyl-lower alkyl-amino, e.g. benzylam-ino, N-methyl- N benzylamino, N-et hyl-N benzylamino, N-ethyl-N-(lphenylethyD-arnino or N methyl N (2 phenylethyl)- amino, phenylor diphenylamino, e.g. p-tolylamino or dip-anisylamino.

In the amino-alkyl group the alkyl portion, either partially or in toto, may also form part of a saturated heterocyclic ring system, of which the amino group is a ring member and is separated from the oxygen atom by at least two carbon atoms. Such amino-alkyl groups are, for example, pyrrolidyl-( 3), l-met hyl-pyrrolidyl-(3), piperidy1-(2) or (3)-methyl, piperidyl-(4), 1-ethylpiperidyl-(4) or 1-methyl-piperidyl-(2) or (3)-methyl.

The quaternaries of the present invention are those containing an additional lower :alkyl or aralkyl group, e.g. one of those mentioned above, on any tertiary nitrogen atom present.

The compounds of the present invention possess valuable pharmacological properties. For example, they cause signs of central nervous system depression, such as muscle relaxation and transquilizing effects. This can be demonstrated, for example, on the mouse, rabbit, cat, dog and monkey at a parenteral dose between about and 200 mg./kg./ day, preferably between about and 50 mg./kg./day or an oral dose between about 50' and 300 mg./kg./ day, preferably between about 100 and 200 mg./kg./day. They are, therefore, useful as central nervous system depressants, skeletal muscle relaxants and tranquilizers.

Particularly useful are compounds of the Formula II:

( mH mAm (II) in which each of the groups R and R stands for hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, nitro, amino, di-lower alkylamino, lower alkanoyl or sulfamyl, R stands for alkyl with 1 to 4 carbon atoms or the radical 0-(CH2) w-Ru (III) in which each of R and R stands for hydrogen, methoxy, fluoro, iodo, chloro nitro, or sulfamy l, n stands for an integer from 2 to 4 and R for di-lower alkylamino or lower alkyleneimino.

The compounds of the present invention are prepared according to methods in themselves known. For example, the process for their preparation consists in:

(a) Reacting a 1-hydroxy-2-R-benzimidazole with a reactively esterified amino-alkanol or (b) Reacting a reactively esterified l-hydroxyalkoxy-Z- R-benzimidazole with ammonia, a primary or secondary amine or (0) Reducing a l-carbamylalkoxy-Z-R-benzimidazole with a complex light metal hydride and, if desired, introducing into a resulting compound any substituent disclosed or converting any su'bstituent present by another disclosed substituent.

In the above compounds a reactively esterified hydroxy group is preferably that esterified with a strong mineral or sulfonic acid, for example, a hydrohalic, e.g. hydrochloric or hydro-bromic acid, or a lower alkaneor benzene-sulfonic acid, e.g. methane-, ethane-, benzeneor p-toluene-sulfonic acid.

A complex light metal hydride, for example, is an alkali metal aluminum or horohydride, such as lithium aluminum hydride or sodium borohydride.

The final products of this invention may be converted into each other by methods in themselves known. Thus, for example, in any primary, secondary or tertiary amine a substituent may be introduced into the amino group, if necessary after conversion into a metal, e.g. alkali metal, derivative thereof. This can be done, for example, by reaction with a reactive ester of an appropriate alcohol, for example, that of a hydrohalic, e.g. hydrochloric, hydrobromic or hydn'odic acid, or a sulfonic acid, such as a lower alkane or benzene sulfonic acid, e.g. methane, ethane or p-toluene sulfonic acid, or an aryl diazonium salt, whereby higher substituted amines or quaternaries are obtained, or by reductive alkylation, i.e. reaction with an appropriate oxo compound and subsequent reduction, or by oxidation, for example with hydrogen peroxide, a percarboxylic or sulfonic acid, e.g. peracetic, per-benzoic, monoperphthalic or p-toluene persulfonic acid, in order to obtain the N-oxides. In compounds, amino-substituted by radicals which can be eliminated by hydrogenolysis, for example, amino-substituted by a-arylalkyl e.g. benzyl radicals, the said radicals can be split off in the usual manher by hydrogenolysis.

The above mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/ or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure. Condensing agents are especially used in the reaction (a) in order to eliminate the acid formed or to convert the hydroxy compound into a salt. They are basic agents, for example, alkali metal hydrides or carbonates, e.g., sodium hydride or potassium carbonate.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free .bases in known manner, for example, with alkalis or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, a-raliphatic, aromatic, or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenyla-cetic, benzoic, aminobenzoic, anthranilic, hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinc, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.

These or other salts of the new compounds, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components may be used in the form of their salts.

Mainly, those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The present invention also comprises the new starting material in which R stands for a cycloaliphatic, araliphatic or aromatic radical. The l-hydroxy-Z-R-benzimidazoles can be obtained by condensation of N-(R- methyl)-2-nitro-anilines in the presence of strong bases, such as an alkali metal hydroxide, e.g., sodium hydroxide, or by reduction of N-(R-car-bonyD-Z-nitroanilines with an alkaline sodium dithionite solution. The starting material in the form of its 3-oxide may be prepared by addition of a compound having the formula R-NO to a benzonitrile-N-oxide containing in at least one of the ortho positions a hydrogen atom. The so obtained 1-hydroxy-Z-R-benzimidazoles may be reacted with a hal-ohydrine in the presence of a basic agent, e.g., those mentioned above, and the resulting l-hydroxyalkyl- Z-R-benzimidazole reactively esterified, for example with a thionyl or sulfonic acid halide, e.g., thionylchloride or bromide, mesyl or tosyl chloride. The l-hydroxy-Z-R- benzimidazoles may also be reacted with reactively esterified hydroxy-alkanoic acid amides in the presence of a basic agent, in order to obtain the l-carbamylalkoxy-Z-R-benzimidazoles. The latter may also be obtained by reacting a halide of a l-carboxyalkoxy-2-R- benzimidazole with ammonia, a primary or secondary amine.

Starting materials or final products that are mixtures of isomers may be separated into simple isomers by methods in themselves known. For example, compounds that contain one or more asymmetrical carbon atoms may be in the form of racemate mixtures, pure racemates, or optical antipodes.

Mixtures of racemates, by virtue of the physicochemical differences between the components, can be resolved into the stereoisomeric pure racemates (diastereoisomers), for example, by chromatography and/or fractional crystallization. Racemic products can likewise be resolved into the optical antipodes, for example, by reaction with optically active acids, separation of the diastereomeric salts and liberation of the bases from the salts.

The compounds of the invention can be used in the free form or in the form of their salts, for example, for the manufacture of pharmaceutical preparations containing the said compounds in admixture with organic or inorganic, solid or liquid pharmaceutical excipients suitable especially for enteral but also for parenteral administration. Suitable excipients are substances that do not react with the new compounds, for example, water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, propylene glycols, white petroleum jelly and other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees or capsules, ,or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or buffers. They may further contain other therapeutically valuable substances. The pharmaceutical preparations are prepared by conventional methods.

The following examples illustrate the invention:

Example 1 6.0 g. of 1-hydroxy-Z-phenyl-benzimidazole are mixed in a 500 ml. Erlenmeyer flask with 75 ml. of dimethyl ,formamide with stirring and the mixture is warmed in a water bath to an internal temperature of 60 C. where it forms a clear yellow solution. Thereupon it is cooled to 30-35 and 1.5 g. of a 53% sodium hydride suspension in mineral oil is added over a 5 minute period. The mixture is stirred at room temperature for 5 minutes and at 5560 internal temperature for 10 minutes and mixed with 25 ml. of toluene. To the reaction mixture, cooled in an ice bath, 17.3 ml. of a solution of dimethylamino-ethyl chloride in toluene (containing 0.193 g./ml.) are added with stirring, stirring is continued for 6 hours and the mixture is stored overnight at room temperature. Hereupon the reaction mixture again is cooled in an ice bath, mixed with 5 ml. of ethanol and ml. of diethyl ether, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in diethyl ether, the solution shaken with 100 ml. of water, the ethereal layer dried over sodium sulfate and evaporated. The remaining yellow oil is dissolved in diethyl ether, the solution cooled in an ice bath and mixed with ethereal hydrochloric acid. The white crystals formed are filtered off and recrystallized from methanol-diethyl ether. There is obtained the 1-(Z-dimethylamino-ethoxy)-2-phenylbenzimidazole dihydrochloride of the formula melting at l77l78 Example 2 4.0 g. of 1-hydroxy-2-phenyl-benzimidazole are dissolved in 50 ml. of dimethyl formamide at 60 with stirring. The clear solution formed is cooled to 40, mixed with 1.0 g. of a 53% sodium hydride suspension in mineral oil, stirred at room temperature for 5 minutes and then at an internal temperature of 55-60 for 10 minutes. Thereupon the reaction mixture is mixed with 25 ml. of toluene, cooled in an ice bath and then mixed with 12 ml. of a solution of diethylamino-ethyl chloride in toluene containing 0.23 g./ml. The clear amber solution is stirred for 6 hours in an ice bath and allowed to stand overnight at room temperature. Thereupon it is cooled in an ice bath, mixed with 5 ml. of 95% ethanol and 100 ml. of diethyl ether and filtered. The filtrate is evaporated to dryness in vacuo, the residue taken up in ether, the solution washed With 100 ml. of water, the ethereal layer dried over sodium sulfate and evaporated. The remaining light yellow oil is dissolved in diethyl ether, the solution cooled in an ice bath and mixed with ethereal hydrochloric acid. The l-(2-diethylamino-ethoxy)-2 phenyl-benzimidazole-dihydrochloride of the formula formed is filtered off and recrystallized from methanoldiethyl ether; M.P. l58l60.

Example 3 5.0 g. of l-hydroxy-Z-(para chloro-phenyl)-benzimidazole are dissolved in 50 ml. of dimethyl formamide with stirring. To the clear pink solution 1.0 g. of a 53% sodium hydride suspension in mineral oil is added at room temperature and stirring is continued at an internal temperature of 45-50 for 10 minutes. A yellow precipitate falls out immediately and upon Warming it dissolves to form a slightly cloudy pale yellow solution.

To the reaction mixture 25 ml. of toluene is added with stirring and then, at ice bath temperature, 11 ml. of a solution of dimethylamino-ethyl chloride in toluene containing 0.193 g./ ml. Stirring is continued for 6 hours and then the reaction mixture is stored overnight at room temperature. Hereupon it is warmed up in a water bath to 50-55 for 2 hours, then cooled in an ice bath and mixed with ml. of 95 ethanol and 200 ml. of ether. The reaction mixture is filtered, the filtrate evaporated under reduced pressure, the residue taken up in ether, the solution Washed with 50 ml. of water, dried and evaporated. The crystalline residue is recrystallized from pentane to give the 1-(Z-dimethylamino-ethoxy)-2-(para chlorophenyl)-benzirnidazole of the formula melting at 85-86. It is dissolved in 25 ml. of methanol, mixed with methanolic hydrochloric acid and the dihydrochloride monohydrate formed is recrystallized from methanol-diethyl ether; M.P. 182-184".

The starting material can be obtained as follows:

32.0 g. of 2-chl0ro-nitrobenzene, 28 g. of para chlorobenzylamine and 14 g. of anhydrous potassium carbonate are mixed in a 500 ml. round bottom 3-neck flask equipped with stirrer, reflux condenser and thermometer. The mixture is heated with stirring to 150 for 2 hours, and then cooled to 80, mixed with 300 ml. of 95% ethanol and refluxed for minutes. The hot reaction mixture is quickly poured into an Erlenmeyer flask, mixed with another 100 ml. of 95% ethanol, heated to the boil and filtered rapidly. From the filtrate immediately crys tals separate and on cooling to room temperature the suspension obtained is filtered. The orange crystals representing 2-nitro-N-(para chloro-benzyl)-aniline are dried for several hours; M.P. 105-108".

22.0 g. of the compound obtained are mixed in a 1000 ml. round bottom flask with 400 ml. of methanol and 17.0 g. of sodium hydroxide, the orange mixture refluxed for 5 hours and allowed to stand overnight at room temperature. Hereupon it is concentrated to about half of its original volume, poured hot into a 1000 ml. beaker, cooled in an ice bath, neutralized to pH 7-8 with approximately 60 ml. of aqueous hydrochloric acid (1:1) and filtered. The filter residue is taken up in 600 ml. of 95% ethanol, the suspension heated to the boil, mixed with 150 ml. of water and hot filtered. From the filtrate crystals separate on cooling which are filtered otf, swirled for several minutes in 300 ml. of acetone and again filtered off. There is obtained the l-hydroxy-2- (para chloro-phenyl)-benzimidazole melting at 216-217.

Example 4 5.0 g, of 1-hydroxy-2-(para chloro-phenyl)-benzimidazole are dissolved in 50 ml. of dimethyl formamide and to the pink solution 1.0 g. of a 53% suspension of sodium hydride in mineral oil are added portionwise with stirring. The reaction mixture is stirred at room temperature for 5 minutes and at 45-50 for 10 minutes. Hereupon 25 ml. of toluene is added, the mixture is then cooled in an ice bath, mixed with 4.4 g. of pyrrolidino-ethyl chloride dissolved in 25 ml. of toluene, stirred for 6 hours and allowed to stand overnight at room temperature. Then it is warmed up to 5055 for one hour whereby it changes from a clear yellow to a colorless liquid, cooled again in an ice bath and mixed with 5 ml. of 95 ethanol and 100 ml. of diethyl ether. The whole is filtered, the filtrate evaporated to dryness in vacuo, the residue taken up in diethyl ether, the solution Washed with 50 ml. of water, dried and evaporated. The viscous oil obtained is recrystallized from pentane to yield the 1-(2-pyriolidinoethoxy)-2-(para chlorophenyl)-benzimidazole of the formula IJ QOI melting at 78-80". It is dissolved in 25 ml. of methanol, the solution acidified with methanolic hydrochloric acid, the dihydrochloride formed filtered 01f and recrystallized from methanol-diethyl ether; M.P. 190*".

Example 5 5.0 g. of 1-hydroxy-2-pheny-l-6-chloro-benzimidazole are dissolved in m1. of dimethyl formamide at 60 with stirring and to the solution 1.0 g. of a 53% sodium hydride suspension in mineral oil is added at 30. Stirring is continued for 10 minutes at 50 and to the mixture 25 ml. of toluene is added. Hereupon it is cooled in an ice bath, mixed with 11 ml. of a dimethylarnino-ethyl chloride solution in toluene containing 0.193 g./ml., stirred for 6 hours and allowed to stand overnight. The reaction mixture is warmed up to 50-55 for one hour, cooled again in an ice bath and mixed with 5 ml. of 95% ethanol and 100 ml. of diethyl ether. The whole is filtered, the filtrate evaporated under reduced pressure, the residue taken up in ether, the solution shaken with 50 m1. of water, dried and evaporated. The so obtained oily 1-(Z-dimethylamino-ethoxy)-2-phenyl-6-chloro benzimidazole of the formula is dissolved in 25 ml. of methanol and converted into its dihydrochloride by the addition of methanolic hydrochloric acid. The salt melts after two recrystallizations from methanol-ether at 192-193 The starting material can be obtained as follows:

The mixture of 38.4 g. of 2,5-dichloro-nitrobenzene, 21.0 g. of benzylamine and 14.0 g. of anhydrous potassium carbonate is heated for 2 hours at 150 with stirring and reflux. To the reaction mixture, cooled to about 300 ml. of ethanol are added, the mixture is refluxed for 10 minutes, diluted with ml. ethanol, again heated to the boil and hot filtered. The N-benzyl-2- nitro-4-chloro-aniline so obtained crystallizes on cooling in an ice bath, it is filtered off and recrystallized from methanol; M.P. 68-69".

24.0 g. of the compound obtained are dissolved in 430 ml. of methanol, 18.5 g. of sodium hydroxide are added and the whole is carefully heated to the boil, refluxed for 5 hours and allowed to stand for 2 days at room temperature. Hereupon it is concentrated to about half of its original volume, cooled in an ice bath and neutralized to pH 7-8 with about 75 m1. of aqueous hydrochloric acid (1:1). The precipitate formed is filtered off, dried, suspended in 1200 ml. of 95% ethanol and 200 ml. of water, the suspension heated to the boil and hot filtered. The white insoluble material is dried overnight on the air and 13.0 g. thereof taken up in 200 ml. of dimethyl formamide. The mixture is heated on the steam bath, filtered hot and upon addition of Water to the filtrate the desired 1-hydroxy-2-pheny l-6-chloro-benzimidazole crystallizes out; M.P. 241 (decomposition).

Example 6 4 g. of 1-hydroxy-2phenyl-S-chloro-benzimidazole are dissolved in 50 ml. of dimethyl formamide at 50, to the solution, cooled to room temperature, 0.8 g. of a 53% sodium hydride suspension in mineral oil is added portionwise and stirring is continued for minutes at room temperature and for minutes at 45-50. The mixture is diluted with 25 ml. of toluene, cooled in an ice bath, mixed with 9 ml. of a dimethyl-amino-ethyl chloride solution in toluene having a concentration of 0.193 g./ml., stirred for 6 hours and allowed to stand overnight. The yellow liquid is heated to 55-60 for one hour, then cooled in an ice bath and mixed with '5 ml. of 95 ethanol and 100 ml. of diethyl ether. The whole is filtered, the filtrate evaporated under reduced pressure, the residue taken up in diethyl ether, the solution washed with 50 ml. of water, dried and evaporated. The yellow oil obtained is dissolved in 25 ml. of methanol, the solution cooled in an ice bath, acidified with methanolic hydrochloric acid, filtered, t-he filter residue recrystallized twice from methanol-diethyl ether and finally washed with acetone. There is obtained the 1-(2-dimethylaminoethoxy)-2-phenyl-5-chloro-benzimidazole dihydrochloride of the formula melting at 182183.

The starting material can be obtained according to the method shown in the previous examples by reaction of 38.4 g. of 2,4-dichloro-nitrobenzene with 21.0 g. of =benzylamine in the presence of anhydrous potassium carlbonate and condensation of 20 g. of the obtained N- benzy1-2-nitro-5-chloro-aniline (M.P. 100-102) in the presence of 15.4 g. of sodium hydroxide. The crude 1- hydroxy 2 phenyl 5 chlor-o benzimidazole precipitates from the neutralized reaction mixture; it is taken up in 650 ml. of 95% ethanol and 150 ml. of water, the mixture is heated to the boil, filtered hot, the filtrate is cooled in an ice bath, mixed with 150 ml. of water and filtered. The filter residue is swirled in 100 ml. of acetone for several minutes and the suspension filtered in order to obtain the pure product melting at 206 with decomposition.

Example 7 Into a solution of 2.73 g. of 1-(2-chloro-ethoxy)-2- phenyl-benzimidazole in 50 ml. of toluene a stream of dimethylamine is bubbled in while stirring and heating the mixture during 3 hours up to the boil. Hereupon the reaction mixture is filtered hot and evaporated under reduced pressure. The residue is taken up in diethyl ether, the solution washed with Water, the ethereal layer dried and evaporated. The remaining oil is dissolved in diethyl ether, the solution cooled in an ice bath and mixed with ethereal hydrochloric acid. The white crystals for-med are filtered oiT and recrystallized from methanol-diethyl ether. There is obtained the 1-(2-dimethylamino-ethyl)-2-phenyl benzimidazole dihydrochloride which is identical with the product obtained according to Example 1.

The starting material can be obtained as follows:

4.0 g. of 1-hydroxy-2-phenyl-benzimidazole are dissolved in 50 ml. of dimethyl formamide at 60 with stirring. To the solution, cooled to 40, 1.0 g. of a 53% sodium hydride suspension in mineral oil is added while stirring and heating the mixture to 60 for 10 minutes. Thereupon it is mixed with 25 ml. of toluene, cooled in an ice bath and again mixed with a solution of 1.6 g. of ethylene chlorohydrin in 25 ml. toluene. The whole is stirred for 6 hours, allowed to stand overnight at room temperature mixed with 5 ml. of 95 ethanol and 100 ml. of diethyl ether and filtered. The filtrate is evaporated under reduced pressure, the residue dissolved in diethyl ether, the solution washed with water, dried and evaporated. The residue is taken up in benzene and added with stirring to 3.0 g. of thionyl chloride in 50 m1. of benzene. The reaction mixture is refluxed for 5 hours with stirring and hereupon evaporated under reduced pressure. The residue is taken up in diethyl ether, the solution shakien with aqueous sodium carbonate, dried and evaporated; the residue represents the desired 1- (Z-chloro-ethoxy) -2-phenyl benzimidazole.

Example 8 In a three necked flask equipped with stirrer and reflux condenser the suspension of 200 ml. of ether and 3.0 g. of lithium aluminum hydride is refluxed for 30 minutes and hereupon the solution of 5.1 g. of [2-phenylbenzimidazolyl-(l)]-oxy-acetyl-ethylamide in 100 ml. of ether is added dropwise to the refluxing mixture. After completed addition (30 minutes) refluxing is continued for 5 hours. The excess of the reducing agent is decomposed by dropwise addition of 5 ml. of ethyl acetate under cooling and stirring, followed by the addition of 50 ml. of water. The aqueous phase is separated, the organic layer filtered, the filtrate extracted with 2 N hydrochloric acid, the extracts made basic with 40% aqueous sodium hydroxide and the mixture extracted with ether. The extracts are Washed with water, saturated sodium chloride solution, dried, filtered and evaporated to give the 1-(2-ethylamino-ethoxy)-2-phenyl benzirnidazole as a viscous oil.

The compound obtained can be converted into the product obtained in Example 2 by reaction with ethyl chloride in a sealed tube and acidifying the residue with ethereal hydrochloric acid.

The starting material can be obtained as follows:

To a solution of 6.3 g. of l-hydroxy-Z-phenyl benzimidazole in 100 ml. of dry toluene 1.5 g. of a 53% sodium hydride suspension in mineral oil is added and the mixture heated to 60 for 10 minutes. It is then cooled in an ice bath and a solution of 5.0 g. of ethyl bromoacetate in 10 ml. of toluene is added while stirring and hereupon the mixture is allowed to stand overnight at room temperature. It is then mixed with 5 ml. of ethanol and ml. of diethyl ether and concentrated under reduced pressure. The residue is taken up in methanol, the mixture filtered, the filtrate mixed with 3.5 g. of potassium hydroxide in 30 ml. of methanol, the mixture allowed to stand at room temperature for two days and then evaporated under reduced pressure. To the residue 100 ml. of water are added and the solution acidified with hydrochloric acid. The whole is extracted with diethyl ether, the extract washed with water, saturated sodium chloride solution, dried, filtered and evaporated. The residue is taken up in diethyl ether, to the solution 5 g. of thionyl-chloride in 20* ml. of benzene are added dropwise, the whole is refluxed for 30 minutes and then evaporated in vacuo, 20 ml. of benzene are added to the residue, again evaporated and this is repeated two times more. The residue is taken up in 50 ml. of diethyl ether, the mixture cooled in an ice bath and stirred while gaseous ethylamine is passed through a wide glass tube, first over the vigorously stirred solution and then under the surface of the reaction mixture until a drop of it shows basic reaction on wet pH paper. Still while cooling and stirring 20 ml. of ethylacetate and 50 ml. of ice water are added, the organic layer separated, washed with water, dried and evaporated under reduced pressure. The obtained benzimidazolyl- (1)-oxy-acetyl-ethylamide is recrystallized several times from benzene-pentane.

Using in the above process ammonia instead of ethylamine and reducing the obtained acetylamide in the analogous manner as the acetyl-ethylamide, the 1-(2- amino-ethoxy)-2-phenyl-benzimidazole is obtained.

Example 9 According to the method shown in Examples 1-6, the following compounds can be prepared by using equivalent amounts of the corresponding reagents.

Example According to the method described in the previous examples, the following compounds can be prepared by using equivalent amounts of the reagents listed below:

calcium stearate, both screened through a No. screen. After mixing for twenty minutes, the granulation is compressed into tablets, each weighing 0.25 g., using inch dies, standard concave punches, uppers bisected, lowers monogrammed.

Preparation of 5000 capsules each containing 0.04 g. of the active ingredient.

Ingredients: G.

1 (2 diethylamino-ethoxy)-2-phenyl-benzimidazole dihydrochloride 5,000

Lactose 85,000

Procedure-The ingredients are blended in a suitable mixer, sieved through a No. screen and again mixed; portions weighing 0.18 g. each, of the resulting mixture are filled into No. 4 capsules.

Example 12 Preparation of 2000 sustained release tablets each containing 0.5 g. of the active ingredient.

Reagents Final Product 1-hydroxy2 (4-methyl-phenyl) -6-mcthyl-benzimidazole 1-hydroxy-2- (4-acety1-pl1cuyl) -benzirnidazo1e 1-hydroxy-2-(4-trifluoromethyl-phenyl) -benzimidazole Dimethylamino-ethyl chloride.

Diethylamino-ethyl chloride s Pyrrolidino-ethyl chloride 1-(2-dimethylarnino-ethoxy)-2-(4-mcthyl-phenyl)-6- methyl-benzimidazole.

l-(-dicfhylamino-ethoxy)-2-(4-acctyl phenyl)-b0uzim- 1 azo c.

1-(2-pyrrolidino-cthoxy)-2-(4-trifluoromcthylphenyD-bcnzimidazole.

1-(2-bromo-ethoxy)-2-phenyl-5-trifiuoromethyl-benzim- Benzylamiuc 1-%-beuzyamoi{1o-ethoxy)-2-phenyl-5-trifluoromcth L idazole. enzimi az e.

1-(2-chl0ro-ethoxy)-2-(3,4,5-trirnethoxy-pheny1)-benzim- Cyclopentylmethylamme 1-(2 cyclopentylmethylammo-ethoxy)-2-(3,4,5-

idazole. trimethoxy-phcnyl)-benznnidazole.

1-(2-chloro-ethoxy)-2-pheny1-6-dimethylaminobenzim- Morpholine 1-g-morplolmf-ethoxy)-2-phenyl-G-dnnethylammoazole. enzmn azo e 1-hydr0xy-2-(4-chlorophenyl)-benzirnidazole N-mcthyl-piperaziuo-ethyl 1-(Z-N-ulethyl-pmcrazmo-cthoxy)-2-(4-chl0ro-pheny1)- chloride. benzimidazole.

B-[2-pheny1-beuzimidazolyl-(1)]-oxy-propionyl-n-butyl amide. l-hydroxy-Z-phenylA,7-dimethyl-henzimidazole Lithium aluminum hydride Piperidinoethyl chloride 4-dimethyl amino-butyl chloride.

N-methyl-2-chloromethylpyrrolidine.

1-(2-n-butylamino-propoxy)-2-phenyl-benzimidazo1e.

1-(2-piperidino-ethoxy)-2-phenyl-4,7-dirnethylbenzimidazole.

1-(4-dimethylamino-hutoxy)-2(4-amino-phcnyl)- benzimidazole.

l-(N-methyl-pyrrolidinyl-(2)-methoxy) 2-(2-methylpyridyl-4)-benzimidazole.

Example 11 Preparation of 160,000 tablets each containing 0.025 g. of the active ingredient.

Ingredients: G.

1 (2 dimethylamino-ethoxy)-2-phenyl-6- chloro-benzimidazole dihydrochloride 4,000 Lactose 28,289 Corn starch 3,410 Confectioners sugar 2,800 Colloidal silica 1,000 Stearic acid powder 400 Calcium stearate 100 Color FD&C yellow No. 5 1

Purified water, q.s.

Procedure-The hydrochloride, the lactose, 2,500.0 g. of the corn starch, the confectioners sugar and the colloidal silica are passed through a No. 16 screen into a mixer and blended at low speed for twenty minutes. The remainder of the corn starch is suspended in a cold solution of the color in 1,000 ml. of purified water, and a paste is formed by gradually adding 4,000 ml. of boiling purified water. The mixed powders are granulated with the above paste, using additional water as required.

Theresulting moist mass is passed through a mill, using a No. 4A screen, placed on trays and dried at 38 C. until the moisture content is between 2 percent and 3 .percent. The granules are broken on a mill through a No. 16 screen, and treated with the stearic acid and the Ingredients 1 (2 diethylamino-ethoxy)-2-phenyl-benzimidazole dihydrochloride g 1000.0

Sterotex -g 88.0

Alginic acid g 42.0

Cellulose acetate phthalate g 300.0

Anhydrous ethanol ml 332.0

Acetone ml 332.0

Procedure.The dihydrochloride, sterotex and alginic acid are passed through a 20 mesh screen and mixed for 30 minutes. The phthalate is dissolved in the ethanol acetone mixture and with the solution the powders are wetted and mixed thoroughly. The granulate is dried with warm air, passed through a 16 mesh screen and compressed into tablets using diameter dies, modified ball punches.

Example 13 13 residue dissolved in ethanol, the solution acidified with ethanolic hydrochloric acid and the crystals formed collected. The so-obtained 1-(3-diethylamino-propoxy)-2- methyl-benzimidazole dihydrochloride of the formula O(CIIz) -N(C2Hs)2 2 is recrystallized from ethanol-diethyl ether and melts at 186.

The starting material is prepared as follows: 36.0 g. 2-nitro-acetanilide are dissolved in 100 ml. 10% aqueous sodium hydroxide whereupon about 120 g. sodium dithionite are added slowly at a temperature below 50 until the color of the mixture remains light yellow. The reaction mixture is stirred at room temperature for three hours, filtered, the filtrate neutralized with concentrated hydrochloric acid, chilled overnight and the precipitated 1-hydroxy-2-methyl-benzimidazole filtered off and dried; it melts at 243245.

Example 14 To the mixture of 5.0 g. 1hydroxy-2-methyl-6-methoxybenzimidazole in 50 ml. dimethylformamide, 1.37 g. of a 53.1% sodium hydride suspension in mineral oil are added while stirring. Stirring is continued for 15 minutes at room temperature and for 30 minutes at 60". T the thick brown suspension 50 ml. toluene are added and then 25 ml. of a toluenic solution containing 179 mg. 2-chloroethyl-dimethylamine per ml. The mixture is heated on a steam bath for two hours and stirred for additional two hours at room temperature. It is then filtered, the filtrate concentrated under reduced pressure, the residue mixed with water, the mixture extracted three times with diethyl ether, the extract dried, filtered and evaporated. To the remaining brown oil ethanolic hydrochloric acid is added and the very hygroscopic salt formed is filtered off and recrystallized from ethanol-diethyl ether using charcoal as decolorant. There is obtained the 1-(Z-dimethylaminoethoxy)-2-methyl-6-methoxy benzimidazole dihydrochloride of the formula N CHsO N CHa melting at 196.

The starting material is prepared as follows: 20 g. 4-acetamido-3-nitro-anisole are dissolved in 500 ml. aqueous sodium hydroxide with stirring and to the solution 50.0 g. sodium dithionate are added below 50. The reaction mixture is stirred overnight, then neutralized with concentrated hydrochloric acid, chilled and filtered to yield the 1-hydroxy-2-methyl-6-methoxy-benzimidazole melting at 211215.

Example To the suspension of 4.0 g. =1-hydroxy-2-phenyl-benzimidazole-3-oxide in 40 ml. dimethylformamide, 0.85 g. of

a 53.1% sodium hydride suspension in mineral oil are added while stirring. Stirring is continued for one hour at room temperature, then 10 ml. toluene are added and hereupon 1.8 g. 3-chloropropyl-dimethylamine in 15 ml. toluene. The reaction mixture is heated on a steam bath for two hours and stirred overnight at room temperature. It is filtered, the filtrate concentrated in vacuo, the concentrate mixed with water and extracted three times with diethyl ether. The extract is dried, filtered and evaporated and the residual red oil dissolved in ethanol. The solution is acidified with ethanolic hydrochloric acid,

chilled and the crystals formed collected, to yield the I dimethylaniline are added while stirring at 0.

l (3-dimethylamino-propoxy)-2-phenyl-benzimidazole-3- oxide hydrochloride of the formula )-(CH2)3N(GHa)2-HOl which melts after recrystallization from ethanol-diethyl ether at l03l05.

The starting material is preparedas follows: Through the well stirred mixture of 30 ml. benzaldoxime and 200 ml. 8N hydrochloric acid, chlorine is bubbled through for 20 minutes at about 0 whereby the mixture turns from a white suspension to a yellow, cloudy layer. The supernatant hydrochloric acid is poured off and the remaining oil is slowly added to ml. 20% aqueous sodium hydroxide and 150 g. ice while stirring and keeping the temperature below 10. After stirring for 15 minutes in an ice bath, the reaction mixture is extracted three times with diethyl ether, and the extract dried and filtered in the cold. To the so-obtained etheral solution of benzonitrile-N-oxide, 19.0 g. nitroso-benzene are added while stirring and stirring is continued from three hours. The tan crystals formed are filtered off and boiled in ethanol for two hours and again filtered off. They are representing the 1 hydroxy-Z-phenyl-benzimidazole-3- oxide melting at 224 (decomp.).

Example 16 To the mixture of 5 .0 g. 1-hydroxy-2-phenyl-6-dimethylamino-benzimidazole6-oxide, 1.2 g. of a 53.1% suspension of sodium hydride in mineral oil are added while stirring and the mixture is stirred for 1 hour on a steam bath and an additional hour at room temperature. Hereupon 10 ml. toluene and 30 ml. 4-(2-chloroethyl)- morpholine are added and the mixture is stirred for 2 hours on a steam bath and during the weekend at room temperature. It is filtered, concentrated in vacuo, the concentrate mixed with water and extracted with diethyl ether. The extract is dried, filtered and evaporated, the residue dissolved in ethanol, the solution acidified with ethanolic hydrochloric acid, chilled and the crystals formed separated. T he so-obtained 1-(2-morpholinoethoxy)-2-phenyl-6-dimethylamino benzimidazole-3- oxide dihydro-chloride of the formula (I)CI-I2CH2N O .2HC1

is recrystallized from ethanol and melts at 174 to 175.

The starting material is prepared as follows: Through the slurry of 30 ml. benzaldoxime in 200 ml. 8N hydrochloric acid, chlorine is bubbled through for 20 minutes keeping the temperature below 0. It is filtered through a sintered glass funnel, the residue is mixed with 100 g. ice and 65 ml. 20% aqueous sodium hydroxide are added at 5 to 0. The whole is stirred until a solid appears and is then extracted with diethylether at 5. The extract is dried, filtered and to the filtrate 15 g. 4-nitroso- The reaction mixture hereupon is stirred for two hours at room temperature, heated on a steam bath for 15 minutes, cooled and filtered. The remaining l-hydroxy-2-phenyl-6- dimethylamino-benzimidazole-3-oxide melts at 8891 (decomp.).

Example 17 0.64 g. sodium hydride (in the form of a mineral oil suspension) are added slowly to a well stirred solution of 3.09 g. 1-hydroxy-2=phenyl-benzimidazole-3-oxide in 30 ml. dimethylformamide. The mixture is heated to 95 for one hour, then cooled and mixed with 15 ml. of a solution of 2-chloroethyl-diethylamine in toluene containing 156 mg. thereof per ml. The reaction mixture is stirred overnight, heated to 95 for two hours, cooled and concentrated to about 30 ml. in vacuo. After the addition of 100 ml. water the solution is extracted with diethyl ether, the extract dried and evaporated to a brown oil. Ethanolic hydrochloric acid is added with chilling, and the product crystallizes upon addition of diethyl ether. It is filtered oil and recrystallized from ethanol-diethyl ether to yield the 1-(2-diethylamino-ethoxy)-2-phenylbenzimidazole-3-oxide hydrochloride of the formula Example 18 3.0 g. of a 53.1% sodium hydride suspension in mineral oil are added during minutes to a stirred and cooled suspension of 10.0 g. 1-hydroxy-2-(4-chloro-phenyl)- benzimidazole in 100 ml. dimethyl-forrnamide. The mixture is heated to 50 for 15 minutes to complete the formation of the sodium salt. Thereupon it is cooled to room temperature and 25 ml. toluene are added followed by 31 ml. of a toluenic solution containing 177 mg. 2- chloroethyldiethylamine per ml. The mixture is stirred at room temperature overnight and heated to 60 for 2 hours in the following morning. It is cooled, ml. ethanol are added to destroy excess sodium hydride, filtered and evaporated to /3 of the original volume. To the concentrate 100 ml. water are added and the mixture is extracted with diethyl ether. The extract is dried, evaporated and the residue acidified with ethanolic hydrochloric acid. The product crystallizes upon cooling and addition of a little diethyl ether. It is recrystallized from ethanol-diethyl ether to yield the 1-(2-diethylaminoethoxy) 2- (4-chloro-phenyl) -benzimidazole dihydrochloride hemihydrate of the formula OCH2-OH:4N(CzH )g-2IIOLlHzO melting at 128130 (de comp).

Example 19 The mixture of 5.1 g. N,N-dimethyl-(2-phenyl-benzimidazolyl-1-oxy)-acetamide and 70 ml. tetrahydrofuran is added dropwise to a stirred suspension of 3.0 g. lithium aluminum hydride in 50 ml. tetrahydrofuran at room temperature and stirring is continued for 5 hours during which time the temperature is raised to reflux. Hereupon 8 m1. ethyl acetate, 3 ml. water, 6 ml. aqueous sodium hydroxide and 9 ml. water are added in this order and the mixture obtained is filtered. The filtrate is extracted with 2 N hydrochloric acid, the extracts made basic with 40% aqueous sodium hydroxide and the mixture extracted with diethyl ether. The extract is washed with water and brine, dried, filtered and evaporated. The residue is dissolved in diethyl ether, the solution cooled and acidified with ethereal hydrochloric acid. The precipitate is filtered off and recrystallized from methanoldiethyl ether to yield the 1-(Z-dimethylamino-ethoxy)-2- phenyl-benzimidazole dihydrochloride which is identical with that obtained according to Example 1.

The starting material is prepared as follows: To the solution of 10.0 g. 1-hydroxy-2-phenyl-benzimidazole in 100 ml. dimethylformamide, 2.0 g. sodium hydride are added slowly while stirring. The mixture is heated on a steam bath for 15 minutes, cooled, diluted with 60 ml.

toluene and mixed with 8.2 g. ethyl bromoacetate in 10 ml. toluene. The mixture is stirred for 14 hours at room temperature and 2 hours on the steam bath. After cooling it is filtered, the filtrate evaporated in vacuo and the residue partitioned between diethyl ether and water. The organic layer is dried, evaporated, the residue dissolved in ethanol, the solution acidified with ethanolic hydrochloric acid, cooled over night and filtered. After recrystallization from ethanol-diethyl ether, the ethyl (2- phenyl-benzimidazolyl 1 oxy)-a cetate hydrochloride hemihydrate melting at 116 is obtained.

7.0 g. thereof are dissolved in 50 ml. ethanol and the solution combined with that of 5.0 -g. potassium hydroxide in 50 ml. aqueous ethanol. The mixture is stirred for 1 /2 hours, acidified with concentrated hydrochloric acid, filtered and the residue recrystallized twice from ethanol-diethyl ether to yield the corresponding free acid melting above 250.

5.0 g. thereof are dissolved in 50 ml. diethyl ether and 5 g. thionyl chloride in 20 ml. benzene are added dropwise and the whole is refluxed for 30 minutes. The mixture is evaporated in vacuo and from the residue 3 times 20 ml. benzene are distilled oif. The residue is dissolved in 50 ml. diethyl ether and the mixture cooled and stirred while gaseous dimethylamine is bubbled through. After 2 hours 30 ml. ethyl acetate are added, the organic layer separated, washed with water, dried and evaporated under reduced pressure to yield the N,N- dimethyl- 2-phenyl-benzimidazolyl-1-oxy) -acetamide.

Example 20 Analogous to the method described in Examples 1 to 6, the following compounds are prepared:

Example 21 According to the method shown in Examples 13 and 14 the following compounds are prepared:

Compound M.P., deg.

1-(2-diethy1amin0-eth0xy)-2-methyl-benzimidazole-ZHCL 186 1-(Z-dimethylamino-ethoxy)-2-methyl-benzimidazole 2HC1 187 1-(2-diethylamino-ethoxy)-2-methyl-6-methoxy-benzirnidazole-2HC1 204-205 1-(ii-diethylnrnino-propoxy)-2-methyl-6-meth0xy-benzimidazole-ZHCI 143-145 Example 22 Following the method described in Examples 15 to 17 the following compoundslisted below are prepared:

Compound M.P., deg.

1-(2-dimethylamino-ethoxy) -2-ph enyl-benzimidazole-3- oxidaHCl -186 1-(2-pyrrolidino-ethoxy) -2-phenyl-benzimidazole-3-o oxide -H 198-199 1-(2-piperidin0-eth oxy) -2-phenylb enzimidazole-3- oxideHCL 197-198 1- (2-morph0lino-ethoxy) -2-phenyl-benzimidazole-3- oxideHCl- 200-202 1-(2-diethylamino-ethoxy) -2-phenyl-6-dirnethylamino-benzimidazole-B-oxide-ZHW 184-185 1-(2-dim ethylamino-eth oxy) -2-phenyl-6-dirnethylaminobenz1midaz0le-3-oxide-2HC1 189-190 17 What is claimed is: 1. A member selected from the group consisting of a compound of the formula Oalkyl-amino in which each of the radicals R and R stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, nitro, amino, di-lower .alkyl-amino and lower alkanoyl, and R stands for a member selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl and cycloalkyl-lower alkyl with 3 to 8 ring carbon atoms, cycloalkenyl and cycloalkenyl-lower alkyl with to 8 ring carbon atoms, aryl-lower alkyl and aryl in which aryl is selected from the group consisting of phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl, (trifiuoromethyl)-phenyl, (amino)-phenyl, (di-lower alkylamino)-phenyl, (lower alkanoyl)-phenyl, pyridyl and (lower alkyl)-pyridyl, the substituent on said aryl being in a position other than ortho, an N-oxide and acid addition salts of these compounds.

2. A member selected from the group consisting of a compound having the formula in which the substituents are in a position other than ortho and are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, di-lower alkyl-amino, lower alkanoyl and sulfamyl, pyridyl and (lower alkyl)-pyridyl, m for an integer from 2 to 7 and Am for a member selected from the group consisting of amino, lower alkylamino, di-lower alkylamino, lower alkyleneimino, mono-aza-lower alkyleneimino, mono-oxa-lower alkyleneimlno, Am being separated from the oxygen atom by at least two carbon atoms, and an acid addition salt thereof.

3. A member selected from the group consisting of a compound having the formula /7\-N KMQ in which the radical R stands for a member selected from the group consisting of hydrogen, methoxy, fluoro, iodo, chloro and nitro, the radical R stands for a member selected from the group consisting of hydrogen, methoxy, fluoro, iodo, chloro and sulfamyl, It stands for an integer from 2 to 4, and R for a member selected from the group consisting of di-lower alkylamino and lower alkyleneimino, and an acid addition salt thereof.

4. A compound as claimed in claim 3, in which each of R and R stands for hydrogen, n for the integer 2 and R for a member selected from the group consisting of dimethylamino and diethylamino.

18 5. A compound as claimed in claim 3, in which R; stands for hydrogen, R for a member selected from the group consisting of 4-chloro, 3-iodo and 4-methoxy, n for the integer 2 and R for a member selected from the group consisting of dimethylamino, diethylamino and pyrrolidino.

6. A compound as claimed in claim 3, in which R stands for a member selected from the group consisting of S-chloro and 6-chloro, R for hydrogen, n for the integer 2 and R for a member selected from the group consisting of dimethylamino and diethylamino.

7. A compound as claimed in claim 3, in which R; stands for hydrogen, R for a member selected from the group consisting of hydrogen and 4-chloro, n: for the integer 3 and R for diethylamino.

8. A compound as claimed in claim 3, in which R stands for 6-nitro, R for a member selected from the group consisting of hydrogen, 4-fluoro, 4-chloro and 4- sulfamyl, n for the integer from 2 to 3 and R for a member selected from the group consisting of dimethylamino and diethylamino.

9. A compound as claimed in claim 2, in which R stands for S-chloro, R for 6-chloro, R for phenyl and --C H -Am for 2-diethylamino-ethyl.

10. A compound as claimed in claim 2, in which both R and R stand for hydrogen, R for 3,4-dichloro-phenyl, C H for a member selected from the group consisting of 1,2-ethylene and 1,3-propylene and Am for a member selected from the group consisting of dimethylamino and diethylamino.

11. A compound as claimed in claim 2, in which R stands for hydrogen, R for a member selected from the group consisting of hydrogen and 6-methoxy, R for methyl, C H for a member selected from the group consisting of 1,2-ethylene and 1,3-propylene and Am for a member selected from the group consisting of dimethylamino and diethylamino.

12. A compound as claimed in claim 2, in which each of R and R stands for hydrogen, R for pyridyl-(4), and the group C H Am for Z-diethyIamino-ethyl.

13. A member selected from the group consisting of a compound having the formula in which R stands for a member selected from the group consisting of hydrogen and dimethylamino, n for an integer from 2 to 3 and Am for a member selected from the group consisting of dimethylamino, diethylamino, pyrrolidino, piperidino and morpholino, and an acid addition salt thereof.

14. A member selected from the group consisting of compounds having the formula in which R stands for a member selected from the group consisting of the radical pyridyl and (lower alkyl)-pyridyl, the radicals R and R stand for a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, nitro, amino, di-lower alkylamino and lower alkanoyl, one of said radicals R and R being other than hydrogen, and the radicals R and R stand for a mem- 19 her selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, dilower alkylamino, lower alkanoyl and sulfamyl, its N- oxides, acid addition and alkali metal salt.

15. A compound as claimed in claim 14, in which R stands for a member selected from the group consisting of cycloalkyl and cycloalkyl-lower alkyl having from 3 to 8 ring-carbon atoms, cycloalkenyl and cycloalkenyllower alkyl having from 5 to 8 ring-carbon atoms, and aryl-lower alkyl in which aryl stands for a member selected from the group consisting of phenyl, (lower alkyl)- phenyl, (lower alkoXy)-phenyl, (halogeno)-phenyl, (tri- 29 fluoromethyD-phenyl, (amino)-phenyl, (di-lower alkylamino)-phenyl, (lower alkan0yl)-phenyl and (sulfamyD- phenyl, its N-oxide, acid addition and alkali metal salt.

WALTER A. MODANCE, Primary Examiner.

ALAN L. ROTMAN, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 